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Case Reports in Infectious Diseases 2023Blackwater fever (BWF) is a severe clinical syndrome occurring as a complication of malarial infection characterized by intravascular hemolysis, hemoglobinuria, and...
BACKGROUND
Blackwater fever (BWF) is a severe clinical syndrome occurring as a complication of malarial infection characterized by intravascular hemolysis, hemoglobinuria, and acute renal failure in people exposed to and, to some extent, in people who were exposed to medications like quinine and mefloquine. The exact pathogenesis of classic BWF remains unclear. The mechanism leading to damage to the red blood cells (RBCs) can be immunologic nonimmunologic, leading to massive intravascular hemolysis. . We present a case of classic blackwater fever in a 24-year-old otherwise previously healthy male without any history of antimalarial prophylaxis use, returning from recent travel to Sierra Leone. He was detected to have malaria in the peripheral smear test. He was treated with artemether/lumefantrine combination therapy. Unfortunately, his presentation was complicated by renal failure and was managed with plasmapheresis and renal replacement therapy.
CONCLUSION
Malaria continues to be a parasitic disease that can have devastating effects and continues to be a challenge globally. Although cases of malaria in the United States are rare and cases of severe malaria, mainly attributed to , are even more uncommon. Care should be taken to retain a high level of suspicion to consider the diagnosis, especially in returning travelers from endemic areas.
PubMed: 37179741
DOI: 10.1155/2023/5796881 -
Neurology India 2023Neuropsychiatric disorders, ranging from mild cognitive impairment to frank psychosis, have been associated with certain parasitic infections. The parasite may cause... (Review)
Review
Neuropsychiatric disorders, ranging from mild cognitive impairment to frank psychosis, have been associated with certain parasitic infections. The parasite may cause damage to the central nervous system in several ways: as a space-occupying lesion (neuro-cysticercosis), alteration of neurotransmitters (toxoplasmosis), generation of the inflammatory response (trypanosomiasis, schistosomiasis), hypovolemic neuronal injury (cerebral malaria), or a combination of these. Certain drugs like quinacrine (mepacrine), mefloquine, quinolone, and interferon alpha which are used to treat these parasitic infections can further cause neuropsychiatric adverse effects. This review summarizes the major parasitic infections that are associated with neuropsychiatric disorders and the pathogenesis involved in their processes. A high index of suspicion for parasitic diseases, especially in endemic areas, should be kept in patients presenting with neuropsychiatric symptoms. A multidimensional approach to identification of the offending parasite using serological, radiological, and molecular tests is required not only to ensure proper and prompt treatment of the primary parasitic infection but also to improve the prognosis of patients by complete resolution of neuropsychiatric symptoms.
Topics: Humans; Parasitic Diseases; Central Nervous System; Mental Disorders; Mefloquine; Cysticercosis
PubMed: 37148042
DOI: 10.4103/0028-3886.375424 -
International Journal of Infectious... Jul 2023This study examined the treatment response of mixed vs single-species Plasmodium falciparum infections to artemisinin-based combination therapies (ACTs). (Randomized Controlled Trial)
Randomized Controlled Trial
Therapeutic response to artemisinin combination therapies among individuals with Plasmodium falciparum single infection vs mixed Plasmodium species infections: a retrospective posthoc analysis in Kisumu County, western Kenya.
OBJECTIVES
This study examined the treatment response of mixed vs single-species Plasmodium falciparum infections to artemisinin-based combination therapies (ACTs).
METHODS
A total of 1211 blood samples collected on days 0, 7, 14, 21, 28, 35, and 42 from 173 individuals enrolled in two randomized ACT efficacy studies were tested for malaria using 18s ribosomal RNA-based real-time polymerase chain reaction. All recurrent parasitemia were characterized for Plasmodium species composition and time to reinfection during 42-day follow-up compared across ACTs.
RESULTS
Day 0 samples had 71.1% (116/163) single P. falciparum infections and 28.2% (46/163) coinfections. A total of 54.0% (88/163) of individuals tested positive for Plasmodium at least once between days 7-42. A total of 19.3% (17/88) of individuals with recurrent infections were infected with a different Plasmodium species than observed at day 0, with 76.5% (13/17) of these "hidden" infections appearing after clearing P. falciparum present at day 0. Artesunate-mefloquine (16.4 hours) and dihydroartemisinin-piperaquine (17.6 hours) had increased clearance rates over artemether-lumefantrine (21.0 hours). Dihydroartemisinin-piperaquine exhibited the longest duration of reinfection prophylaxis. Cure rates were comparable across each species composition.
CONCLUSION
No differences in clearance rates were found depending on whether the infection contained species other than P. falciparum. Significantly longer durations of protection were observed for individuals treated with dihydroartemisinin-piperaquine.
Topics: Humans; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Combinations; Kenya; Malaria; Malaria, Falciparum; Plasmodium falciparum; Quinolines; Reinfection; Retrospective Studies
PubMed: 37061211
DOI: 10.1016/j.ijid.2023.04.008 -
BMC Medicine Apr 2023Whole sporozoite immunization under chemoprophylaxis (CPS regime) induces long-lasting sterile homologous protection in the controlled human malaria infection model... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Whole sporozoite immunization under chemoprophylaxis (CPS regime) induces long-lasting sterile homologous protection in the controlled human malaria infection model using Plasmodium falciparum strain NF54. The relative proficiency of liver-stage parasite development may be an important factor determining immunization efficacy. Previous studies show that Plasmodium falciparum strain NF135 produces relatively high numbers of large liver-stage schizonts in vitro. Here, we evaluate this strain for use in CPS immunization regimes.
METHODS
In a partially randomized, open-label study conducted at the Radboudumc, Nijmegen, the Netherlands, healthy, malaria-naïve adults were immunized by three rounds of fifteen or five NF135-infected mosquito bites under mefloquine prophylaxis (cohort A) or fifteen NF135-infected mosquito bites and presumptive treatment with artemether/lumefantrine (cohort B). Cohort A participants were exposed to a homologous challenge 19 weeks after immunization. The primary objective of the study was to evaluate the safety and tolerability of CPS immunizations with NF135.
RESULTS
Relatively high liver-to-blood inocula were observed during immunization with NF135 in both cohorts. Eighteen of 30 (60%) high-dose participants and 3/10 (30%) low-dose participants experienced grade 3 adverse events 7 to 21 days following their first immunization. All cohort A participants and two participants in cohort B developed breakthrough blood-stage malaria infections during immunizations requiring rescue treatment. The resulting compromised immunizations induced modest sterile protection against homologous challenge in cohort A (5/17; 29%).
CONCLUSIONS
These CPS regimes using NF135 were relatively poorly tolerated and frequently required rescue treatment, thereby compromising immunization efficiency and protective efficacy. Consequently, the full potential of NF135 sporozoites for induction of immune protection remains inconclusive. Nonetheless, the high liver-stage burden achieved by this strain highlights it as an interesting potential candidate for novel whole sporozoite immunization approaches.
TRIAL REGISTRATION
The trial was registered at ClinicalTrials.gov under identifier NCT03813108.
Topics: Adult; Animals; Humans; Antimalarials; Artemether, Lumefantrine Drug Combination; Immunization; Insect Bites and Stings; Malaria; Malaria Vaccines; Plasmodium falciparum; Sporozoites
PubMed: 37024868
DOI: 10.1186/s12916-023-02788-9 -
Pathogens (Basel, Switzerland) Mar 2023We have previously reported 1,2,6,7-tetraoxaspiro [7.11]nonadecane (N-89) as a promising antimalarial compound. In this study, we evaluated the effect of transdermal...
We have previously reported 1,2,6,7-tetraoxaspiro [7.11]nonadecane (N-89) as a promising antimalarial compound. In this study, we evaluated the effect of transdermal therapy (tdt) of N-89 in combination (tdct) with other antimalarials as an application for children. We prepared ointment formulas containing N-89 plus another antimalarial drug, specifically, mefloquine, pyrimethamine, or chloroquine. In a 4-day suppressive test, the ED values for N-89 alone or combined with either mefloquine, pyrimethamine, or chloroquine were 18, 3, 0.1, and 3 mg/kg, respectively. Interaction assays revealed that N-89 combination therapy showed a synergistic effect with mefloquine and pyrimethamine, but chloroquine provoked an antagonistic effect. Antimalarial activity and cure effect were compared for single-drug application and combination therapy. Low doses of tdct N-89 (35 mg/kg) combined with mefloquine (4 mg/kg) or pyrimethamine (1 mg/kg) gave an antimalarial effect but not a cure effect. In contrast, with high doses of N-89 (60 mg/kg) combined with mefloquine (8 mg/kg) or pyrimethamine (1 mg/kg), parasites disappeared on day 4 of treatment, and mice were completely cured without any parasite recurrence. Our results indicated that transdermal N-89 with mefloquine and pyrimethamine provides a promising antimalarial form for application to children.
PubMed: 36986320
DOI: 10.3390/pathogens12030398 -
International Journal For Parasitology.... Apr 2023Alveolar echinococcosis (AE) is caused by infection with the fox tapeworm E. multilocularis. The disease affects humans, dogs, captive monkeys, and other mammals, and it...
Alveolar echinococcosis (AE) is caused by infection with the fox tapeworm E. multilocularis. The disease affects humans, dogs, captive monkeys, and other mammals, and it is caused by the metacestode stage of the parasite growing invasively in the liver. The current drug treatment is based on non-parasiticidal benzimidazoles. Thus, they are only limitedly curative and can cause severe side effects. Therefore, novel and improved treatment options for AE are needed. Mefloquine (MEF), an antimalarial agent, was previously shown to be effective against E. multilocularis in vitro and in experimentally infected mice. However, MEF is not parasiticidal and needs improvement for successful treatment of patients, and it can induce strong neuropsychiatric side-effects. In this study, the structure-activity relationship and mode of action of MEF was investigated by comparative analysis of 14 MEF derivatives. None of them showed higher activity against E. multilocularis metacestodes compared to MEF, but four compounds caused limited damage. In order to identify molecular targets of MEF and effective derivatives, differential affinity chromatography combined with mass spectrometry was performed with two effective compounds (MEF, MEF-3) and two ineffective compounds (MEF-13, MEF-22). 1'681 proteins were identified that bound specifically to MEF or derivatives. 216 proteins were identified as binding only to MEF and MEF-3. GO term enrichment analysis of these proteins and functional grouping of the 25 most abundant MEF and MEF-3 specific binding proteins revealed the key processes energy metabolism and cellular transport and structure, as well as stress responses and nucleic acid binding to be involved. The previously described ferritin was confirmed as an exclusively MEF-binding protein that could be relevant for its efficacy against E. multilocularis. The here identified potential targets of MEF will be further investigated in the future for a clear understanding of the pleiotropic effects of MEF, and improved therapeutic options against AE.
Topics: Humans; Mice; Animals; Dogs; Mefloquine; Echinococcus multilocularis; Parasites; Echinococcosis; Antiparasitic Agents; Mammals
PubMed: 36921443
DOI: 10.1016/j.ijpddr.2023.03.002 -
The Journal of Infectious Diseases Aug 2023Mpox virus (MPXV) is a zoonotic orthopoxvirus and caused an outbreak in 2022. Although tecovirimat and brincidofovir are approved as anti-smallpox drugs, their effects...
BACKGROUND
Mpox virus (MPXV) is a zoonotic orthopoxvirus and caused an outbreak in 2022. Although tecovirimat and brincidofovir are approved as anti-smallpox drugs, their effects in mpox patients have not been well documented. In this study, by a drug repurposing approach, we identified potential drug candidates for treating mpox and predicted their clinical impacts by mathematical modeling.
METHODS
We screened 132 approved drugs using an MPXV infection cell system. We quantified antiviral activities of potential drug candidates by measuring intracellular viral DNA and analyzed the modes of action by time-of-addition assay and electron microscopic analysis. We further predicted the efficacy of drugs under clinical concentrations by mathematical simulation and examined combination treatment.
RESULTS
Atovaquone, mefloquine, and molnupiravir exhibited anti-MPXV activity, with 50% inhibitory concentrations of 0.51-5.2 μM, which was more potent than cidofovir. Whereas mefloquine was suggested to inhibit viral entry, atovaquone and molnupiravir targeted postentry processes. Atovaquone was suggested to exert its activity through inhibiting dihydroorotate dehydrogenase. Combining atovaquone with tecovirimat enhanced the anti-MPXV effect of tecovirimat. Quantitative mathematical simulations predicted that atovaquone can promote viral clearance in patients by 7 days at clinically relevant drug concentrations.
CONCLUSIONS
These data suggest that atovaquone would be a potential candidate for treating mpox.
Topics: Humans; Atovaquone; Mefloquine; Monkeypox virus
PubMed: 36892247
DOI: 10.1093/infdis/jiad058 -
Journal of Personalized Medicine Jan 2023Malaria was eradicated in Taiwan in 1952; however, imported malaria cases are reported every year. The subtropical climate in Taiwan permits mosquito propagation and...
Malaria was eradicated in Taiwan in 1952; however, imported malaria cases are reported every year. The subtropical climate in Taiwan permits mosquito propagation and possible outbreaks of mosquito-borne diseases. The aim of this study was to investigate travelers' compliance and side effects of malaria prophylaxis to prevent a malaria outbreak in Taiwan. In this prospective study, we enrolled travelers who visited our travel clinic before going to malarious areas. A total of 161 questionnaires were collected and analyzed. Associations between the occurrence of side effects and compliance with antimalarial drugs were analyzed. Adjusted odds ratios were calculated after adjusting for potential risk factors in multiple logistic regression analysis. Of the 161 enrolled travelers, 58 (36.0%) reported side effects. Insomnia, somnolence, irritability, nausea, and anorexia were associated with poor compliance. Mefloquine was not associated with more neuropsychological side effects than doxycycline. Multiple logistic regression analysis showed that chemoprophylaxis compliance was affected by a younger age, visiting friends and relatives, visiting the travel clinic more than 1 week before the trip, and preferring to use the same antimalarial regimen on the next trip. Our findings could provide information to travelers besides labeled side effects to improve compliance with malaria prophylaxis and consequently help to prevent malaria outbreaks in Taiwan.
PubMed: 36836413
DOI: 10.3390/jpm13020179 -
International Journal of Molecular... Feb 2023Precision medicine gives individuals tailored medical treatment, with the genotype determining the therapeutic strategy, the appropriate dosage, and the likelihood of... (Review)
Review
Precision medicine gives individuals tailored medical treatment, with the genotype determining the therapeutic strategy, the appropriate dosage, and the likelihood of benefit or toxicity. Cytochrome P450 (CYP) enzyme families 1, 2, and 3 play a pivotal role in eliminating most drugs. Factors that affect CYP function and expression have a major impact on treatment outcomes. Therefore, polymorphisms of these enzymes result in alleles with diverse enzymatic activity and drug metabolism phenotypes. Africa has the highest CYP genetic diversity and also the highest burden of malaria and tuberculosis, and this review presents current general information on CYP enzymes together with variation data concerning antimalarial and antituberculosis drugs, while focusing on the first three CYP families. Afrocentric alleles such as CYP2A6*17, CYP2A6*23, CYP2A6*25, CYP2A6*28, CYP2B6*6, CYP2B6*18, CYP2C8*2, CYP2C9*5, CYP2C9*8, CYP2C9*9, CYP2C19*9, CYP2C19*13, CYP2C19*15, CYP2D6*2, CYP2D6*17, CYP2D6*29, and CYP3A4*15 are implicated in diverse metabolic phenotypes of different antimalarials such as artesunate, mefloquine, quinine, primaquine, and chloroquine. Moreover, CYP3A4, CYP1A1, CYP2C8, CYP2C18, CYP2C19, CYP2J2, and CYP1B1 are implicated in the metabolism of some second-line antituberculosis drugs such as bedaquiline and linezolid. Drug-drug interactions, induction/inhibition, and enzyme polymorphisms that influence the metabolism of antituberculosis, antimalarial, and other drugs, are explored. Moreover, a mapping of Afrocentric missense mutations to CYP structures and a documentation of their known effects provided structural insights, as understanding the mechanism of action of these enzymes and how the different alleles influence enzyme function is invaluable to the advancement of precision medicine.
Topics: Humans; Antimalarials; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP2C8; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP3A; Alleles; Cytochrome P-450 CYP2B6; Antitubercular Agents; Cytochrome P-450 CYP2C9; Cytochrome P-450 Enzyme System
PubMed: 36834793
DOI: 10.3390/ijms24043383 -
PloS One 2023Declining in susceptibility of Plasmodium falciparum to mefloquine is reported in South-East Asia. A revisiting on mefloquine pharmacokinetics-pharmacodynamics (PK/PD)...
BACKGROUND
Declining in susceptibility of Plasmodium falciparum to mefloquine is reported in South-East Asia. A revisiting on mefloquine pharmacokinetics-pharmacodynamics (PK/PD) could assist in finding new appropriate dosage regimens in combination with artesunate as a three-day course treatment.
OBJECTIVE
This study aimed to investigate promising alternative artesunate-mefloquine combination regimens that are effective for the treatment of patients with mefloquine-sensitive and resistant P. falciparum malaria.
METHODS
Data collected during 2008-2009 from 124 patients with uncomplicated P. falciparum malaria were included in the analysis, 90 and 34 patients with sensitive and recrudescence response, respectively. All patients were treated with a three-day combination of artesunate-mefloquine. Population PK-PD models were developed. The developed models were validated with clinically observed data. Simulations of clinical efficacy of alternative mefloquine regimens were performed based on mefloquine sensitivity, patients' adherence and parasite biomass.
RESULTS
The developed PK/PD models well described with clinically observed data. For mefloquine-resistant P. falciparum, a three-day standard regimen of artesunate-mefloquine is suitable (>50% efficacy) only when the level of parasite sensitivity was < 1.5-fold of the cut-off level (IC50 < 36 nM). For mefloquine-sensitive parasite with IC50 < 23.19 nM (0.96-fold), all regimens provided satisfactory efficacy. In the isolates with IC50 of 24 nM, regimen-I is recommended. Curative treatment criteria for mefloquine and artesunate were C336h (>408 ng.mL-1) or Cmax/IC50 (>130.1 g.m/M), and Cmax/IC50 (>381.2 g.m/M), respectively.
CONCLUSIONS
Clinical use of a three-day standard artesunate-mefloquine is suitable only when the IC50 of P. falciparum isolates is lower than 36 nM. Otherwise, other ACT regimens should be replaced. For mefloquine-sensitive parasite, a dose reduction is recommended with the IC50 is lower than 23.19 nM.
Topics: Humans; Antimalarials; Mefloquine; Artesunate; Artemisinins; Malaria, Falciparum; Plasmodium falciparum; Drug Therapy, Combination; Sesquiterpenes
PubMed: 36821622
DOI: 10.1371/journal.pone.0282099